JP6616780B2 - Controlled release compositions and methods - Google Patents
Controlled release compositions and methods Download PDFInfo
- Publication number
- JP6616780B2 JP6616780B2 JP2016556754A JP2016556754A JP6616780B2 JP 6616780 B2 JP6616780 B2 JP 6616780B2 JP 2016556754 A JP2016556754 A JP 2016556754A JP 2016556754 A JP2016556754 A JP 2016556754A JP 6616780 B2 JP6616780 B2 JP 6616780B2
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- JP
- Japan
- Prior art keywords
- hlb value
- ethylcellulose
- aid
- fusion aid
- surfactant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000000203 mixture Substances 0.000 title claims description 48
- 238000000034 method Methods 0.000 title claims description 44
- 238000013270 controlled release Methods 0.000 title claims description 31
- 230000004927 fusion Effects 0.000 claims description 46
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- 238000000576 coating method Methods 0.000 claims description 36
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- 230000008569 process Effects 0.000 claims description 16
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- 239000007787 solid Substances 0.000 claims description 14
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Classifications
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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Description
1つの態様では、本発明は、エチルセルロースコーティング層を有する放出制御固体剤形を製造する方法に向けられ、この層は3から8のHLB値を有する有機エステルである融合助剤(coalescing agent)を含む。そのような融合助剤の使用は、コーティングプロセス後の更なる硬化工程を必要とせずに効果的な放出制御コーティングの形成を可能とする。他の態様では、この発明は、製造されるコーティングされた剤形だけでなく、そのような方法において有益な水性分散液にも関する。 In one aspect, the present invention is directed to a method of making a controlled release solid dosage form having an ethylcellulose coating layer, the layer comprising a coalescing agent that is an organic ester having an HLB value of 3 to 8. Including. The use of such a fusion aid allows the formation of an effective controlled release coating without the need for further curing steps after the coating process. In another aspect, the invention relates not only to the coated dosage forms that are produced, but also to aqueous dispersions that are useful in such methods.
放出制御剤形は、即時放出剤形の投与と比較すると、剤形の投与後に長時間の薬理作用を提供するように設計される。このような持続的な応答は、即時放出及び短時間作用の製品では得られない多くの固有の治療上の利点を与える。 Controlled release dosage forms are designed to provide prolonged pharmacological action after administration of the dosage form as compared to administration of the immediate release dosage form. Such a sustained response provides many inherent therapeutic benefits not available with immediate release and short acting products.
当該技術分野で知られている放出制御剤形は、コーティングされたビーズ、ペレット又は球状体、コーティングされたカプセル、コーティングされたタブレット及びイオン交換樹脂を含み、活性薬剤の徐放はコーティング層又はマトリックス製剤を通した活性薬剤の浸透を介して実現され、薬剤の放出を遅くする。 Controlled release dosage forms known in the art include coated beads, pellets or spheroids, coated capsules, coated tablets and ion exchange resins, where the sustained release of the active agent is a coating layer or matrix This is achieved through the penetration of the active agent through the formulation and slows the release of the drug.
全ての放出制御剤形の本質的な特徴は剤形の安定性である。医薬剤形の安定性は、特定の一連の条件下での特定の容器内の貯蔵の間における、その物理的、化学的、微生物学的、治療学的、薬学的及び毒物学的特性の恒常性を示す。安定性試験は、新薬承認申請(New Drug Applications)(NDAs)及び新薬治験許可申請(Investigational New Drug Applications)(INDs)だけでなく、U.S.P.の適正製造基準(Good Manufacturing Practices)(GMPs)でも必要とされる。 An essential feature of all controlled release dosage forms is the dosage form stability. The stability of a pharmaceutical dosage form is the constant of its physical, chemical, microbiological, therapeutic, pharmaceutical and toxicological properties during storage in a specific container under a specific set of conditions. Showing gender. Stability studies include not only New Drug Applications (NDAs) and New Drug Drug Applications (INDs), but also U.S.A. S. P. Also required by Good Manufacturing Practices (GMPs).
疎水性ポリマーは、放出制御剤形の開発のために、タブレット、カプセル、坐薬、球状体、ビーズ又はマイクロスフィアをコーティングするフィルム形成剤として使用されてきた。従来技術では、これらの疎水性コーティングは、有機溶液、擬似ラテックス又は懸濁液の形態中で製剤化されることが知られている。これらのポリマーの大部分は水に不溶性であるので、有機溶媒中のポリマー溶液を(ビーズ又はタブレット等の)個々の薬剤形態上に噴霧して、溶媒はコーティングプロセスの間に蒸発させる。しかし、蒸発した溶媒は環境汚染問題をもたらす。加えて、有機溶媒を用いたコーティング製剤は、燃焼性、発がん性及び安全性に関して固有の問題を有する。 Hydrophobic polymers have been used as film formers to coat tablets, capsules, suppositories, spheroids, beads or microspheres for the development of controlled release dosage forms. In the prior art, it is known that these hydrophobic coatings are formulated in the form of organic solutions, pseudolatexes or suspensions. Since most of these polymers are insoluble in water, polymer solutions in organic solvents are sprayed onto individual drug forms (such as beads or tablets) and the solvents are allowed to evaporate during the coating process. However, the evaporated solvent poses environmental pollution problems. In addition, coating formulations using organic solvents have inherent problems with respect to flammability, carcinogenicity and safety.
これらの理由から、放出制御製剤を調製するためには、不溶性ポリマーのラテックス又は擬似ラテックスをベースとする水性ポリマーコーティング組成物を使用することが望ましい。望ましい放出制御コーティングを製造するためにうまく用いられるラテックスの中には、エチルセルロースをベースとするものがある。しかし、このようなエチルセルロースコーティングの貯蔵安定性を高めるために、望ましくは追加のプロセス工程が使用される。従って、例えば、特許文献1(Liら)には、エチルセルロース又は類似のポリマー材料の水性分散液から製造されたコーティングの貯蔵安定性は、高湿度下でコア基板をコーティングして、その後加熱処理工程を用いて乾燥させるプロセスによって向上され得ることが記載されている。このプロセスは望ましい放出制御コーティングを作り出すが、特殊な機器の使用及び/又は監視を必要として製造時間を増加させる追加プロセス(加熱)工程の使用を必要とし得る。従って、当該プロセスがそのような特定の機器の使用及び/又はそのような追加のプロセス工程の実行を必要としない、エチルセルロースの水性分散液からの効果的な放出制御コーティングの製造方法を有することが望まれる。 For these reasons, it is desirable to use aqueous polymer coating compositions based on latex or pseudolatex of insoluble polymers to prepare controlled release formulations. Some latexes that are successfully used to produce desirable controlled release coatings are those based on ethylcellulose. However, additional process steps are desirably used to increase the storage stability of such ethylcellulose coatings. Thus, for example, in US Pat. No. 6,057,049 (Li et al.), The storage stability of a coating made from an aqueous dispersion of ethyl cellulose or similar polymer material is described by coating a core substrate under high humidity and then a heat treatment step. It can be improved by a process of drying using While this process produces the desired controlled release coating, it may require the use of additional process (heating) steps that require the use of specialized equipment and / or monitoring and increase manufacturing time. Accordingly, the process may have a method for producing an effective controlled release coating from an aqueous dispersion of ethylcellulose that does not require the use of such specific equipment and / or the execution of such additional process steps. desired.
融合助剤はしばしば封止剤及び塗料の製造に使用されるが、そのような製剤から得られるコーティングは一般的に不浸透性となるように設計される。従って、例えば、特許文献2(Quinn)には、(エチルセルロースを含む)水性ポリマー分散液をベースとした不浸透性コーティング又はフィルムの形成に適した組成物が記載されており、この分散液は、プロピレングリコールモノステアレート等の融合助剤を任意に含み得る。やや同様のものでは、特許文献3(Lynchら)には、塗料、封止剤等に有用な、水不溶性ポリマーの水性分散液中における融合助剤としてのエチレングリコール及び/又は(プロピレングリコールモノラウレートを含む)プロピレングリコールの特定の脂肪酸エステルの使用について記載されている。このように、3から8のHLB値を有する有機エステルである融合助剤を使用するエチルセルロース分散液から剤形のための放出制御コーティングが製造され得るということは予想し得ないことである。 While fusion aids are often used in the manufacture of sealants and paints, the coatings obtained from such formulations are generally designed to be impermeable. Thus, for example, Patent Document 2 (Quinn) describes a composition suitable for the formation of an impermeable coating or film based on an aqueous polymer dispersion (including ethylcellulose), which dispersion is Optionally, a fusion aid such as propylene glycol monostearate may be included. Somewhat similar, Patent Document 3 (Lynch et al.) Describes ethylene glycol and / or (propylene glycol monolaur as fusion aids in aqueous dispersions of water-insoluble polymers useful for paints, sealants, etc. The use of certain fatty acid esters of propylene glycol (including the rate) is described. Thus, it is unexpected that a controlled release coating for a dosage form can be made from an ethylcellulose dispersion using a fusion aid that is an organic ester having an HLB value of 3 to 8.
1つの態様では、本発明は、放出制御固体剤形を製造する方法に関し、この方法は、(i)水、(ii)エチルセルロース、(iii)イオン性界面活性剤、及び、(iv)3から8のHLB値を有する有機エステルである融合助剤を含む水性懸濁液を、コーティングを形成するように、活性成分を含む固体コア(solid core)に適用することを含む。 In one aspect, the invention relates to a method of making a controlled release solid dosage form comprising: (i) water, (ii) ethylcellulose, (iii) an ionic surfactant, and (iv) 3 Applying an aqueous suspension comprising a fusion aid, which is an organic ester having an HLB value of 8, to a solid core containing the active ingredient to form a coating.
別の態様では、この発明は、そのようなプロセスにより製造される、放出制御固体剤形に関する。 In another aspect, the invention relates to a controlled release solid dosage form produced by such a process.
また別の態様では、本発明は、放出制御コーティングを製造するのに適した水性懸濁液組成物に関し、この組成物は、(a)水、(b)エチルセルロース、(c)イオン性界面活性剤、及び、(iv)3から8のHLB値を有する有機エステルである融合助剤、を含む。 In yet another aspect, the present invention relates to an aqueous suspension composition suitable for producing a controlled release coating comprising: (a) water, (b) ethylcellulose, (c) ionic surfactant. And (iv) a fusion aid that is an organic ester having an HLB value of 3 to 8.
1つの態様では、本発明は、放出制御固体剤形を製造する方法に関し、この方法は、(i)水、(ii)エチルセルロース、(iii)イオン性界面活性剤、及び、(iv)3から8のHLB値を有する有機エステルである融合助剤を含む水性懸濁液を、コーティングを形成するように、活性成分を含む固体コアに適用することを含む。 In one aspect, the invention relates to a method of making a controlled release solid dosage form comprising: (i) water, (ii) ethylcellulose, (iii) an ionic surfactant, and (iv) 3 Applying an aqueous suspension comprising a fusion aid that is an organic ester having an HLB value of 8 to a solid core containing the active ingredient to form a coating.
米国薬局方協会(The United States Parmacopeial Convention)(“USP”)一般章<711>溶解(General Chapter<711>Dissolution)で特定されているプロセスに従って装置2(Paddle Apparatus)を用いてin vitroで測定した時、薬剤の即時放出は、15分未満において薬剤の85%より多くが放出されるものと多くの場合みなされる。ここで使用される放出制御とは、即時放出ではない任意の放出プロファイルを包含し、並びに、上記のUSPプロトコルに従って測定された場合、15分より長い時間における85%未満の薬剤放出、及び、例えば2時間、4時間、6時間若しくは8から12時間の任意の時間又はそれより長い時間全てにおける100%の薬剤放出を含む。ここで使用される放出制御は、持続放出及び徐放出を意味する。 In vitro measurement using apparatus 2 (Paddle Apparatus) according to the process specified in The United States Pharmacopeial Convention (“USP”) General Chapter <711> Dissolution (General Chapter <711> Dissolution). As such, immediate release of the drug is often considered to release more than 85% of the drug in less than 15 minutes. Controlled release as used herein includes any release profile that is not immediate release, and less than 85% drug release over a period of 15 minutes, as measured according to the above USP protocol, and, for example, Includes 100% drug release at any time of 2 hours, 4 hours, 6 hours or 8-12 hours or all longer. Controlled release as used herein means sustained release and sustained release.
本発明の実施に使用される固体コアは活性成分を含み、ビース、タブレット又は任意の他の従来の固体剤形の形態であり得る。コーティングされ得る形態の中には、ノンパレル(nonpareil)層薬剤、微結晶性セルロースビーズ及び押し出し加工/球形化により調製されたビーズがある。本発明の放出制御コーティングがタブレットに適用される場合、タブレットコアは、任意の薬学的に許容される不活性医薬充填剤(希釈剤)材料と共に、活性成分を含み得る。この材料は、スクロース、デキストロース、ラクトース、微結晶性セルロース、キシリトール、フルクトース、ソルビトール及びそれらの混合物等を含むが、これらに限定されない。また、カルシウム又はマグネシウム石鹸を含む任意の一般的に許容される薬学的潤滑剤の有効量を、タブレットコア成分の圧縮前の上述の賦形剤の成分に添加してもよい。最も好ましくは、固体剤形の約0.5重量%から3重量%の量におけるステアリン酸マグネシウムである。 The solid core used in the practice of the present invention contains the active ingredient and may be in the form of a bead, tablet or any other conventional solid dosage form. Among the forms that can be coated are nonpareil layer drugs, microcrystalline cellulose beads and beads prepared by extrusion / spheronization. When the controlled release coating of the present invention is applied to a tablet, the tablet core may comprise the active ingredient together with any pharmaceutically acceptable inert pharmaceutical filler (diluent) material. This material includes, but is not limited to, sucrose, dextrose, lactose, microcrystalline cellulose, xylitol, fructose, sorbitol and mixtures thereof. Also, an effective amount of any generally acceptable pharmaceutical lubricant, including calcium or magnesium soap, may be added to the above-described excipient components prior to compression of the tablet core component. Most preferred is magnesium stearate in an amount of about 0.5% to 3% by weight of the solid dosage form.
活性成分は、放出制御組成物中で有益に使用される任意の薬学的、治療学的又は栄養補助的な活性成分を含んでもよい。本発明の組成物中に使用され得る活性成分は、水溶性及び水不溶性化合物の両方を含む。実例として、使用され得る活性成分の非限定的な実施例は、抗ヒスタミン剤(例えば、ジメンヒドリネート、ジフェンヒドラミン、クロルフェニラミン及びデクスクロルフェニラミンマレエート)、鎮痛剤(例えば、アスピリン、コデイン、モルヒネ、ジヒドロモルフォン、オキシコドン等)、抗炎症剤(例えば、ナプロキシン、ジクロフェナク、インドメタシン、イブプロフェン、アセトアミノフェン、アスピリン、スリンダク)、胃腸剤及び制吐剤(例えば、メトクロプラミド)、抗てんかん剤(例えば、フェニトイン、メプロバメート及びニトラゼパム)、血管拡張剤(例えば、ニフェジピン、パパベリン、ジルチアゼム及びニカルジリン)、鎮咳剤及び去痰剤(例えば、コデインホスフェート)、抗喘息剤(例えば、テオフィリン)、抗痙攣剤(例えば、アトロピン、スコポラミン)、ホルモン(例えば、インスリン、レパリン)、利尿剤(例えば、エルタクリミン酸、ベンドロフルアジド)、抗降圧剤(例えば、プロプラノロール、クロニジン)、気管支拡張剤(例えば、アルブテロール)、抗炎症性ステロイド(例えば、ヒドロコルチゾン、トリアムシノロン、プレドニゾン)、抗生物質(例えば、テトラサイクリン)、痔疾用剤、睡眠剤、向精神剤、止瀉剤、粘液溶解剤、鎮静剤、充血抑止剤、緩下剤、制酸剤、ビタミン、(フェニルプロパノールアミン等の食欲抑制剤を含む)刺激剤を含む。上記のリストは他の活性成分を除外することを意図していない。 The active ingredient may include any pharmaceutically, therapeutically or nutraceutical active ingredient beneficially used in a controlled release composition. Active ingredients that can be used in the compositions of the present invention include both water-soluble and water-insoluble compounds. Illustratively, non-limiting examples of active ingredients that can be used include antihistamines (eg, dimenhydrinate, diphenhydramine, chlorpheniramine and dexchlorpheniramine maleate), analgesics (eg, aspirin, codeine, morphine, Dihydromorphone, oxycodone, etc.), anti-inflammatory agents (eg, naproxin, diclofenac, indomethacin, ibuprofen, acetaminophen, aspirin, sulindac), gastrointestinal and antiemetics (eg, metoclopramide), antiepileptic agents (eg, phenytoin, meprobamate) And nitrazepam), vasodilators (eg, nifedipine, papaverine, diltiazem and nicardiline), antitussives and expectorants (eg, codeine phosphate), anti-asthmatic agents (eg, theophylline) Anticonvulsants (eg atropine, scopolamine), hormones (eg insulin, reparin), diuretics (eg eruclamic acid, bendrofluazide), antihypertensive agents (eg propranolol, clonidine), bronchodilators (eg , Albuterol), anti-inflammatory steroids (eg, hydrocortisone, triamcinolone, prednisone), antibiotics (eg, tetracycline), hemorrhoids, hypnotics, psychotropic agents, antidiarrheals, mucolytic agents, sedatives, antihypertensives Laxatives, antacids, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine). The above list is not intended to exclude other active ingredients.
放出制御コーティングを製造するために適しておりこの発明のプロセスで使用される本発明の水性懸濁液は、エチルセルロース、イオン性界面活性剤、及び、3から8のHLB値の有機エステルである融合助剤を含む。 The aqueous suspension of the present invention suitable for producing a controlled release coating and used in the process of this invention is a fusion that is ethyl cellulose, an ionic surfactant, and an organic ester with an HLB value of 3 to 8 Contains auxiliaries.
典型的な水性分散液は、20重量%から40重量%のエチルセルロースを含み得る。市販のエチルセルロースの水性分散液は、例えば、エフエムシーコーポレーションからアクアコート(登録商標)ECDの名称で販売されているものが利用可能であり、カラコン(Colorcon)からシュアリース(登録商標)の名称で販売されているものが利用可能である。アクアコート(登録商標)ECDは、24.5重量%から29.5重量%のエチルセルロース、0.9重量%から1.7重量%のラウリル硫酸ナトリウム及び1.7重量%から3.3重量%のセチルアルコールを含む水性分散液である。 A typical aqueous dispersion may contain 20 wt% to 40 wt% ethylcellulose. Commercially available aqueous dispersions of ethyl cellulose are available, for example, under the name Aquacoat (registered trademark) ECD from FM Corporation, and under the name of Surely (registered trademark) from Colorcon. What is sold is available. Aquacoat® ECD is 24.5% to 29.5% by weight ethylcellulose, 0.9% to 1.7% by weight sodium lauryl sulfate and 1.7% to 3.3% by weight. An aqueous dispersion containing cetyl alcohol.
本発明で用いられる融合助剤は3から8のHLB値を有する。好ましくは、融合助剤は3.5から7のHLB値を有し、最も好ましくは、融合助剤は4から5のHLB値を有する。“HLB値”の用語は、親水性と親油性の両方の基を含む両親媒性分子の親水性−親油性バランスを示す。親水性−親油性バランス(HLB)値は、これらの基の比率の尺度として使用される。HLB値は非イオン性分子について算出され、その値は0から20の範囲となる。10より上のHLB値を有する化合物は水に親和性を有し(親水性)、10より下のHLB値を有するものは油の親和性(親油性)を有する。イオン性界面活性剤は最近相対的なHLB値が割り当てられ、数の範囲を60まで広げることを可能にする。 The fusion aid used in the present invention has an HLB value of 3 to 8. Preferably, the fusion aid has an HLB value of 3.5 to 7, and most preferably the fusion aid has an HLB value of 4 to 5. The term “HLB value” refers to the hydrophilic-lipophilic balance of an amphiphilic molecule containing both hydrophilic and lipophilic groups. The hydrophilic-lipophilic balance (HLB) value is used as a measure of the ratio of these groups. The HLB value is calculated for nonionic molecules and the value ranges from 0 to 20. Compounds having an HLB value above 10 have an affinity for water (hydrophilicity) and those having an HLB value below 10 have an oil affinity (lipophilicity). Ionic surfactants have recently been assigned a relative HLB value, allowing the number range to be extended to 60.
本発明の実施に用いられる融合助剤は、典型的に、式RCOOR1を有する有機エステルであり、式中、RはC5−C17の炭化水素部分であり、且つR1は前記エステルが3から8のHLB値を有するのに十分な親水性を有する有機部分である。Rは脂肪族であっても又は芳香族基を含んでもよく、飽和又は不飽和であってもよい。好ましくは、RはC5−C17の飽和又は不飽和脂肪族炭化水素部分である。ここで使用される場合、“有機部分”の用語は、1又は複数の水素、酸素、硫黄又は窒素原子で置換されていてもよい炭素をベースとする部分を示す。 The fusion aid used in the practice of the present invention is typically an organic ester having the formula RCOOR 1 where R is a C 5 -C 17 hydrocarbon moiety and R 1 is the ester An organic moiety having sufficient hydrophilicity to have an HLB value of 3 to 8. R may be aliphatic or may contain an aromatic group and may be saturated or unsaturated. Preferably, R is a saturated or unsaturated aliphatic hydrocarbon moiety C 5 -C 17. As used herein, the term “organic moiety” refers to a carbon-based moiety that may be substituted with one or more hydrogen, oxygen, sulfur or nitrogen atoms.
好ましい融合助剤の第1の種類は、式RCOOCH2CH(CH3)OHであり、式中、RはC5−C17の飽和又は不飽和脂肪族炭化水素部分であるプロピレングリコールモノエステルである。この類型の好ましい融合助剤は、プロピレングリコールモノカプリレート及びプロピレングリコールモノラウレートを含み、プロピレングリコールモノラウレートが特に好ましい。実際の手法として、プロピレングリコールモノエステルが使用される時、そのような化合物は典型的にその対応するジエステルとの混合物となっている。好ましくは、融合助剤がプロピレングリコールモノラウレートを含む時、そのような混合物は少なくとも40重量%のモノエステルを含み、より好ましくはそのような混合物は少なくとも90重量%のモノエステルを含む。 A first type of preferred coalescing aid is the formula RCOOCH 2 CH (CH 3 ) OH, where R is a propylene glycol monoester that is a C 5 -C 17 saturated or unsaturated aliphatic hydrocarbon moiety. is there. Preferred fusion aids of this type include propylene glycol monocaprylate and propylene glycol monolaurate, with propylene glycol monolaurate being particularly preferred. In practice, when propylene glycol monoester is used, such a compound is typically a mixture with its corresponding diester. Preferably, when the fusion aid comprises propylene glycol monolaurate, such a mixture contains at least 40% by weight monoester, more preferably such a mixture contains at least 90% by weight monoester.
好ましい融合助剤の第2の種類は、式中、RがC5−C17の飽和又は不飽和脂肪族炭化水素であるソルビタンエステルであり、特にソルビタンモノオレエートである。 The second type of preferred coalescing agent is wherein, R is a sorbitan ester is a saturated or unsaturated aliphatic hydrocarbon of C 5 -C 17, in particular sorbitan monooleate.
融合助剤は、典型的に、エチルセルロースポリマーの総重量に基づき、4重量%と30重量%との間の量、好ましくは9重量%と15重量%との間の量で存在する。 The fusion aid is typically present in an amount between 4% and 30% by weight, preferably between 9% and 15% by weight, based on the total weight of the ethylcellulose polymer.
このような水性懸濁液中に用いられる界面活性剤は、薬学的に許容され、貯蔵間の分散液の安定性を効果的に維持する任意のイオン性界面活性剤であってもよい。そのような界面活性剤はカチオン性又はアニオン性界面活性剤であってもよいが、典型的にはアニオン性界面活性剤が使用される。使用され得るアニオン性界面活性剤の例は、アルカリ金属及びアンモニウム石鹸(例えば、オレイン酸、ステアリン酸及びリシノール酸等の長鎖脂肪酸のナトリウム塩、カリウム塩又はアンモニウム塩)、二価及び三価の金属石鹸、アミン石鹸、アルキルサルフェート、並びに、アルキルホスフェートを挙げることができる。P.MuthuprasanaらのBasic and Potential Applications of Surfactants−A Review,Int.J.PharmaTech.Res.2009,1(4)を参照されたい。好ましい界面活性剤はアルキルサルフェートを含み、ラウリル硫酸ナトリウムが特に好ましい。 The surfactant used in such aqueous suspensions may be any ionic surfactant that is pharmaceutically acceptable and that effectively maintains the stability of the dispersion during storage. Such surfactants may be cationic or anionic surfactants, but typically anionic surfactants are used. Examples of anionic surfactants that can be used are alkali metal and ammonium soaps (eg, sodium, potassium or ammonium salts of long chain fatty acids such as oleic acid, stearic acid and ricinoleic acid), divalent and trivalent Mention may be made of metal soaps, amine soaps, alkyl sulfates and alkyl phosphates. P. Muthuprasana et al., Basic and Potential Applications of Surfactants-A Review, Int. J. et al. PharmaTech. Res. See 2009, 1 (4). Preferred surfactants include alkyl sulfates, with sodium lauryl sulfate being particularly preferred.
界面活性剤は、懸濁液の安定性を維持するために十分な量で使用され、典型的に、懸濁液の総重量に基づき、0.2重量%と2重量%との間、好ましくは0.9重量%と1.7重量%との間で含まれる。 The surfactant is used in an amount sufficient to maintain the stability of the suspension and is typically between 0.2% and 2% by weight, preferably based on the total weight of the suspension. Is comprised between 0.9% and 1.7% by weight.
水性分散液と一緒での可塑剤の使用がフィルムの物理的特性を更に改善し得ることが見出されているので、本発明に使用される水性ポリマーコーティング組成物は適切な可塑剤の有効量を含むことが好ましい。適切な可塑剤の例は、ジブチルセバケート、ジエチルフタレート、トリエチルシトレート、トリブチルシトレート、プロピレングリコール、ポリエチレングリコール及びトリアセチン等の水不溶性の可塑剤を含むが、他の水不溶性の可塑剤(アセチル化モノグリセリド、フタレートエステル、ヒマシ油等)が使用されることも可能である。トリエチルシトレートは特に好ましい可塑剤である。可塑剤は、典型的に、エチルセルロースポリマーの総重量に基づき、15重量%と40重量%との間の量、好ましくは20重量%と30重量%との間の量で存在する。 Since it has been found that the use of a plasticizer with an aqueous dispersion can further improve the physical properties of the film, the aqueous polymer coating composition used in the present invention is an effective amount of a suitable plasticizer. It is preferable to contain. Examples of suitable plasticizers include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, propylene glycol, polyethylene glycol and triacetin, but other water insoluble plasticizers (acetyl Monoglycerides, phthalate esters, castor oil, etc.) can also be used. Triethyl citrate is a particularly preferred plasticizer. The plasticizer is typically present in an amount between 15% and 40% by weight, preferably between 20% and 30% by weight, based on the total weight of the ethylcellulose polymer.
本発明の実施に使用される水性懸濁液は、フィルム形成剤、可塑剤及び溶媒系(即ち、水)に加えて、優雅さと製品の識別性を提供するために、好ましくは着色剤を含む。色は、治療上の活性成分の溶液に、水性ポリマーコーティング組成物の代わり、又は水性ポリマーコーティング組成物に加えて、添加されてもよい。例えば、水溶性ポリマー溶液に剪断しながら色を添加して、その後可塑化アクアコート(登録商標)ECDエチルセルロース分散液に追加する時に低剪断を利用することによって、アルコール又はプロピレングリコールをベースとする着色分散液、粉砕アルミニウムレーキ及び二酸化チタン等の乳白剤の使用を介して、アクアコート(登録商標)ECDエチルセルロース分散液に色を加えることができる。あるいは、本発明の製剤に色を提供する任意の適切な方法を用いてもよい。 The aqueous suspension used in the practice of the present invention preferably includes a colorant to provide elegance and product discrimination in addition to the film former, plasticizer and solvent system (ie, water). . Color may be added to the solution of the therapeutically active ingredient instead of or in addition to the aqueous polymer coating composition. For example, coloring based on alcohol or propylene glycol by adding color while shearing to a water-soluble polymer solution and then utilizing low shear when added to the plasticized Aquacoat® ECD ethylcellulose dispersion Color can be added to Aquacoat® ECD ethylcellulose dispersions through the use of opacifiers such as dispersions, ground aluminum lakes and titanium dioxide. Alternatively, any suitable method for providing color to the formulations of the present invention may be used.
水性懸濁液は、当業者に公知の機器を使用して固体コアに適用され得る。従って、水性懸濁液は、ウルスターインサートを備えたボトムスプレー流体床コーターを用いてビーズ上にコーティングされ得る。トップスプレー及びタンジェンシャルスプレー流体床並びに変性させたコーティングパンもまた、ビーズコーティングのために使用され得る。サイドベント及び従来のコーティングパンは、タブレットコーティングのために使用され得る。 The aqueous suspension can be applied to the solid core using equipment known to those skilled in the art. Thus, the aqueous suspension can be coated on the beads using a bottom spray fluid bed coater with a Wurster insert. Top spray and tangential spray fluid beds and modified coating pans can also be used for bead coating. Side vents and conventional coating pans can be used for tablet coating.
毛管力に抵抗性がある緩く詰まった又は付着性の粒子は、焼結又は融合によるコヒーレントフィルムの形成が後に続く、基板表面上の粒子の最密充填に依存する、フィルム形成メカニズムを妨害するので、例えば、基板上での噴霧又は流動化による適用前又は適用間に、ラテックス又は擬似ラテックス粒子が、分散液中で凝集、凝結又は凝固しないことが重要である。 Loosely packed or adherent particles that are resistant to capillary forces interfere with the film formation mechanism, which depends on close packing of particles on the substrate surface, followed by the formation of a coherent film by sintering or fusion. It is important that the latex or pseudolatex particles do not agglomerate, coagulate or coagulate in the dispersion, for example before or during application by spraying or fluidizing on the substrate.
この発明の固体剤形は、上述したように、固体コアを水性分散液でコーティングすることにより形成される。水性懸濁液は、所望の放出速度を有するコーティングが得られるような量で適用される。このコーティング厚さは、関連する特定の活性成分、所望の放出速度、未コーティングの基板の粒子サイズ及び形状、その表面の平滑性等を含む、多数の要因に基づき選択される。一般的に、形成されるフィルムの厚さは5ミクロン以上であるべきである。5ミクロン未満の厚さのフィルムは、不十分なフィルム強度及び完全性を有することがあり、これはフィルム特性に経時的な変化を引き起こし得る。具体的な上限は無いが、フィルムが厚すぎる場合、放出速度は過度に遅くなり得る。典型的に、コーティングは、50μmと250μmとの間の厚さだろう。 The solid dosage form of this invention is formed by coating the solid core with an aqueous dispersion as described above. The aqueous suspension is applied in such an amount that a coating having the desired release rate is obtained. This coating thickness is selected based on a number of factors, including the particular active ingredient involved, the desired release rate, the particle size and shape of the uncoated substrate, the smoothness of its surface, and the like. In general, the thickness of the film formed should be 5 microns or more. Films less than 5 microns thick may have insufficient film strength and integrity, which can cause changes in film properties over time. There is no specific upper limit, but if the film is too thick, the release rate can be too slow. Typically, the coating will be between 50 and 250 μm thick.
本発明の実施に使用される水性懸濁液は、任意の特定の湿度要件又は追加の加熱工程無しに効果的な放出制御剤形を形成するが、所望される場合そのような条件/工程を用いてもよい。 The aqueous suspension used in the practice of the present invention forms an effective controlled release dosage form without any specific humidity requirements or additional heating steps, but if desired, such conditions / processes It may be used.
ここに記載される各々の成分、化合物、置換基又はパラメータは、単独での、又は、ここに記載される他の成分、化合物、置換基又はパラメータのありとあらゆる1又は複数との組み合わせでの使用について開示されているものとして解釈されることは理解されるべきである。 Each component, compound, substituent or parameter described herein is for use alone or in combination with any one or more of the other components, compounds, substituents or parameters described herein. It should be understood that it is to be construed as disclosed.
ここに記載される各々の成分、化合物、置換基又はパラメータについての各々の量/値又は量/値の範囲は、ここに記載される任意の他の成分(1又は複数)、化合物(1又は複数)、置換基(1又は複数)又はパラメータ(1又は複数)について記載される各々の量/値又は量/値の範囲と組み合わせて開示されているものとしても解釈されること、並びに、ここに記載される2以上の成分(1又は複数)、化合物(1又は複数)、置換基(1又は複数)又はパラメータ(1又は複数)についての量/値又は量/値の範囲の任意の組み合わせもまた、上述のように、本記載の目的のために互いに組み合わせて開示されていることは理解されるべきである。 Each amount / value or amount / value range for each component, compound, substituent or parameter described herein may be any other component (s), compound (1 or To be construed as being disclosed in combination with each quantity / value or range of quantities / values described for the substituent (s), substituent (s) or parameter (s), and Any combination of amounts / values or ranges of amounts / values for two or more of the component (s), compound (s), substituent (s) or parameter (s) described in It should also be understood that as described above, they are disclosed in combination with each other for the purposes of this description.
ここに記載される各々の範囲の各々の下限は、同じ成分、化合物、置換基又はパラメータについてここに記載される各々の範囲の各々の上限との組み合わせについて開示されているものとして解釈されることは、更に理解されるべきである。従って、2つの範囲の開示は、各々の範囲の各々の下限と各々の範囲の各々の上限との組み合わせに由来する4つの範囲の開示として解釈される。3つの範囲の開示は、各々の範囲の各々の下限の各々の範囲の各々の上限との組み合わせ等に由来する9つの範囲の開示として解釈される、等である。更に、本開示又は実施例中に記載の成分、化合物、置換基又はパラメータの特定の量/値は、範囲の下限又は上限のいずれかの開示として解釈され、そのため、その成分、化合物、置換基又はパラメータについての範囲を形成するために、本出願の他の場所に記載されている同じ成分、化合物、置換基又はパラメータについての範囲又は特定の量/値の任意の他の下限又は上限と組み合わせることができる。 Each lower limit of each range described herein is to be interpreted as being disclosed for the same component, compound, substituent or parameter in combination with each upper limit of each range set forth herein. Should be further understood. Accordingly, the disclosure of the two ranges is to be construed as a disclosure of the four ranges derived from the combination of each lower limit of each range and each upper limit of each range. The disclosure of the three ranges is to be construed as a disclosure of nine ranges derived from a combination of each lower limit of each range with each upper limit of each range, and so forth. Furthermore, specific amounts / values of components, compounds, substituents or parameters described in this disclosure or examples are to be construed as disclosure of either the lower or upper limits of the range, and as such components, compounds, substituents Or combined with any other lower or upper limit of the range or specific amount / value for the same component, compound, substituent or parameter described elsewhere in this application to form a range for the parameter be able to.
以下の実施例はこの発明の原理に従って本発明を説明するために提供されるが、添付の特許請求の範囲に示されるものを除き、いかなる方法においても本発明を限定するものとして解釈されるべきではない。 The following examples are provided to illustrate the invention in accordance with the principles of the invention, but should be construed as limiting the invention in any manner except as set forth in the appended claims. is not.
(実施例1)
最低フィルム形成温度(“MFFT”)についてのプロピレングリコールモノエステルの効果
24重量%のトリエチルシトレート(“TEC”)(エチルセルロースポリマーの重量に基づく)と共に、以下の表1に示される重量で示される融合助剤(エチルセルロース固体の重量に基づく)を添加することによって、アクアコート(登録商標)ECD−30をベースとするいくつかの水性懸濁液を調製した。脱イオン水を添加して、懸濁液を15%固体に希釈した。
(Example 1)
Effect of propylene glycol monoester on minimum film formation temperature (“MFFT”), shown with the weights shown in Table 1 below, along with 24 wt% triethyl citrate (“TEC”) (based on the weight of ethyl cellulose polymer) Several aqueous suspensions based on Aquacoat® ECD-30 were prepared by adding a fusion aid (based on the weight of ethylcellulose solids). Deionized water was added to dilute the suspension to 15% solids.
そのような懸濁液のMFFTを、MFFTバーモデル90を用いて試験した。MFFTバーをプリセットし、予測されるMFFT値に応じて所望の温度範囲を選択した。この研究では、範囲3(5℃から18℃)、範囲4(15℃から33℃)又は範囲5(23℃から50℃)を使用した。400ミクロンキューブアプリケーターを用いて、温かい温度側から冷たい温度側へ製剤を適用し、フィルムが形成された後のMFFT値を読み取った。 The MFFT of such a suspension was tested using the MFFT bar model 90. The MFFT bar was preset and the desired temperature range was selected according to the predicted MFFT value. In this study, range 3 (5 ° C to 18 ° C), range 4 (15 ° C to 33 ° C) or range 5 (23 ° C to 50 ° C) were used. Using a 400 micron cube applicator, the formulation was applied from the warm side to the cold side and the MFFT value after the film was formed was read.
次の融合助剤を評価した。
・PGML−プロピレングリコールモノラウレート。ラウログリコール(登録商標)90(Gattefosse)(HLB 4.3)。
・PGMC−プロピレングリコールモノカプリレート。カプリオール(登録商標)90(Gattefosse)(HLB 6)。
・PGML/PGDL−51.5%プロピレングリコールモノラウレート及び48.5%プロピレングリコールジラウレートを含む混合物。
The following fusion aids were evaluated.
-PGML-propylene glycol monolaurate. Lauroglycol® 90 (Gattefose) (HLB 4.3).
-PGMC-propylene glycol monocaprylate. Capriol 90 (Gattefosse) (HLB 6).
A mixture comprising PGML / PGDL-51.5% propylene glycol monolaurate and 48.5% propylene glycol dilaurate.
このような試験の結果を以下の表1に要約する。 The results of such tests are summarized in Table 1 below.
上記のデータは、プロピレングリコールモノエステルを含む融合助剤を含む3つの懸濁液の全てが低下したMFFTを示したということを示す。製剤は、MFFTより高い温度で適用された時、均質となっており、滑らかなフィルムを生成した。 The above data shows that all three suspensions containing a fusion aid containing propylene glycol monoester showed reduced MFFT. The formulation became homogeneous and produced a smooth film when applied at temperatures higher than MFFT.
(実施例2)
MFFTについての他の類似した化学物質の効果
実施例1のプロセスを用いて、融合助剤として類似した化合物を用いていくつかの懸濁液を調製した。このような化合物は、9重量%の割合で添加された(エチルセルロース固体の重量に基づく)。評価した化合物は、PGDL(プロピレングリコールジラウレート、HLB 2)、GMC(グリセリルモノカプリレート、HLB 8.3)、GML(グリセリルモノオレエート、HLB 2.8)及びTGDS(トリグリセロールジイソステアレート、HLB 10−13)とした。PGDLが製剤のMFFTを効果的に低下させなかった一方、GMC、GML及びTGDSは製剤と良好な融和性を持っていなかった。長時間にわたって混合した後でさえも、製剤中に粘着性の残留物が見られた。MFFTバー上のフィルムは滑らかでなく、又は透明ではなかった。
(Example 2)
Effect of other similar chemicals on MFFT Using the process of Example 1, several suspensions were prepared using similar compounds as fusion aids. Such compounds were added at a rate of 9% by weight (based on the weight of ethyl cellulose solids). The compounds evaluated were PGDL (propylene glycol dilaurate, HLB 2), GMC (glyceryl monocaprylate, HLB 8.3), GML (glyceryl monooleate, HLB 2.8) and TGDS (triglycerol diisostearate, HLB 10-13). While PGDL did not effectively reduce the MFFT of the formulation, GMC, GML and TGDS did not have good compatibility with the formulation. Even after mixing for a long time, a sticky residue was seen in the formulation. The film on the MFFT bar was not smooth or transparent.
(実施例3)
テオフィリン放出速度についてのPGMLの効果
テオフィリンペレット(70%テオフィリン、Spansules Pharma Tech)を、融合助剤有り又は無しで、24%TEC可塑化アクアコート(登録商標)ECDコーティング製剤を用いてコーティングした。TECの使用基準はエチルセルロースポリマーの重量に基づく。コリコート(登録商標)IRを孔形成剤として使用した。コリコート(登録商標)IR対エチルセルロースの重量比は15/85に維持した。コーティング製剤を作る時、PGMLをアクアコート(登録商標)ECD−30中に添加した。
(Example 3)
Effect of PGML on theophylline release rate Theophylline pellets (70% theophylline, Spanish Pharma Tech) were coated with a 24% TEC plasticized Aquacoat® ECD coating formulation with or without a fusion aid. The TEC usage criteria is based on the weight of the ethylcellulose polymer. Kollicoat® IR was used as the pore former. The weight ratio of Kollicoat® IR to ethylcellulose was maintained at 15/85. When making the coating formulation, PGML was added into Aquacoat® ECD-30.
コーティングプロセスの条件は、入口温度65℃、噴霧量10.0g/分、露点10℃、空気流量65m3/時間、霧化圧2.0バールとした。コーティング条件は、融合助剤有り又は無しで同様にした。8.9%PGML製剤は何の異常も観察されずにテオフィリンペレット上にコーティングされた一方で、27%PGML製剤はコーティングプロセスの間いくらか粘着性を有していた。 The coating process conditions were an inlet temperature of 65 ° C., a spray rate of 10.0 g / min, a dew point of 10 ° C., an air flow rate of 65 m 3 / hour, and an atomization pressure of 2.0 bar. The coating conditions were the same with or without a fusion aid. The 8.9% PGML formulation was coated on theophylline pellets without any abnormalities, while the 27% PGML formulation was somewhat sticky during the coating process.
ペレットの溶解プロファイルを、100rpmの攪拌速度及び271nmUV吸光度を有するpH7.5の0.05Mリン酸緩衝液900mL体積で、USP装置1を用いて測定した。表2は、(後硬化無しの)未硬化ペレット及び(75%相対湿度下60℃で2時間後硬化した)硬化ペレットのテオフィリン溶解プロファイルを示す。具体的には、ペレットから放出された薬剤のパーセンテージを列挙する。 The dissolution profile of the pellet was measured using USP apparatus 1 with a 900 mL volume of 0.05M phosphate buffer pH 7.5 having a stirring speed of 100 rpm and 271 nm UV absorbance. Table 2 shows theophylline dissolution profiles of uncured pellets (without post-curing) and cured pellets (post-cured for 2 hours at 60 ° C. under 75% relative humidity). Specifically, the percentage of drug released from the pellet is listed.
上記結果は、本発明の組成物が、高湿度及び/又は高温での硬化を必要とせずに、所望の放出制御特性を示すことを指し示している。 The above results indicate that the composition of the present invention exhibits the desired controlled release properties without the need for curing at high humidity and / or high temperatures.
(実施例4)
テオフィリン放出速度についてのソルビタンモノオレエートの効果
実施例3のプロセス及び材料を用いて、融合助剤として(PGMLではなく)12%ソルビタンモノオレエートを含むタブレットを製造した。未硬化及び硬化(60℃で2時間)の両方での薬剤放出のパーセンテージを、実施例3で記載したように測定した。このような試験の結果を表3に要約する。
(Example 4)
Effect of sorbitan monooleate on theophylline release rate The process and materials of Example 3 were used to make tablets containing 12% sorbitan monooleate (not PGML) as a fusion aid. The percentage of drug release both uncured and cured (2 hours at 60 ° C.) was measured as described in Example 3. The results of such tests are summarized in Table 3.
上記結果は、本発明の組成物が、高湿度及び/又は高温での硬化を必要とせずに、所望の放出制御特性を示すことを指し示している。 The above results indicate that the composition of the present invention exhibits the desired controlled release properties without the need for curing at high humidity and / or high temperatures.
(実施例5)
ジルチアゼム放出速度についてのPGMLの効果
ジルチアゼムHClペレット(60%ジルチアゼムHCl、Ria International)を、融合助剤有り又は無しで、アクアコート(登録商標)ECDを用いてコーティングして、エチルセルロース固体をベースとする24%TECを用いて可塑化した。コーティングプロセスの条件は、入口温度65℃、噴霧量10.0g/分、露点10℃、空気流量65m3/時間、霧化圧2.0バールとした。コーティングしたペレットを湿度制御無しで60℃で2時間硬化した。入口温度は、多量の融合助剤が使用された時に粘着性となるのを避けるため、50℃から55℃に低下させた。ジルチアゼムHClペレットの溶解プロファイルを、100rpmの攪拌速度及び237nmUV吸光度を有する脱イオン水900mL体積で、USP装置1を用いて測定した。このような試験の結果を以下の表4に要約する。
(Example 5)
Effect of PGML on Diltiazem Release Rate Diltiazem HCl pellets (60% Diltiazem HCl, Ria International) are coated with Aquacoat® ECD with or without a fusion aid and based on ethylcellulose solids Plasticized with 24% TEC. The coating process conditions were an inlet temperature of 65 ° C., a spray rate of 10.0 g / min, a dew point of 10 ° C., an air flow rate of 65 m 3 / hour, and an atomization pressure of 2.0 bar. The coated pellets were cured at 60 ° C. for 2 hours without humidity control. The inlet temperature was reduced from 50 ° C. to 55 ° C. to avoid becoming sticky when a large amount of coalescing aid was used. The dissolution profile of diltiazem HCl pellets was measured using USP apparatus 1 with 900 mL volume of deionized water having a stirring speed of 100 rpm and 237 nm UV absorbance. The results of such tests are summarized in Table 4 below.
上記結果は、本発明の組成物が、高湿度及び/又は高温での硬化を必要とせずに、所望の放出制御特性を示すことを指し示している。 The above results indicate that the composition of the present invention exhibits the desired controlled release properties without the need for curing at high humidity and / or high temperatures.
(実施例6)
ジルチアゼム放出速度についてのソルビタンモノオレエートの効果
融合助剤として(PGMLではなく)12%ソルビタンモノオレエートが使用されることを除き、実施例5に記載のプロセス及び材料を用いてペレットを製造した。未硬化並びに硬化(60℃で2時間及び75%相対湿度下60℃で2時間)の両方での薬剤放出のパーセンテージを、実施例5で記載したように測定した。このような試験の結果を以下の表5に要約する。
(Example 6)
Effect of sorbitan monooleate on diltiazem release rate Pellets were produced using the process and materials described in Example 5 except that 12% sorbitan monooleate (rather than PGML) was used as a fusion aid. . The percentage of drug release both uncured and cured (2 hours at 60 ° C. and 2 hours at 60 ° C. under 75% relative humidity) was measured as described in Example 5. The results of such tests are summarized in Table 5 below.
(実施例7)
テオフィリン放出速度についてのプロピレングリコールモノラウレート及びジラウレート混合物の効果
約94重量%PGMLを含むPGMLの代わりに51.5重量%PGML及び48.5重量%PGDL(プロピレングリコールジラウレート)を含むPGML及びPGDLの混合物が使用されることを除き、実施例3のプロセスを繰り返した。使用されたPGML及びPGDLの総重量は、エチルセルロース含有量に基づき8.9%であった。このような評価の結果を以下の表6に要約する。
(Example 7)
Effect of propylene glycol monolaurate and dilaurate mixture on theophylline release rate PGML and PGDL containing 51.5 wt% PGML and 48.5 wt% PGDL (propylene glycol dilaurate) instead of PGML containing about 94 wt% PGML The process of Example 3 was repeated except that a mixture was used. The total weight of PGML and PGDL used was 8.9% based on the ethylcellulose content. The results of such evaluation are summarized in Table 6 below.
上記結果は、51.5重量%/48.5重量%のPGML/PGDL混合物がよく作用していることを証明している。 The above results demonstrate that the 51.5 wt% / 48.5 wt% PGML / PGDL mixture is working well.
(実施例8)
テオフィリンの放出速度についてのPGMCの効果
PGMLの代わりにプロピレングリコールモノカプリレート(PGMC)を用いて実施例3のプロセスを行った。このような評価の結果を表7に要約する。
(Example 8)
Effect of PGMC on theophylline release rate The process of Example 3 was performed using propylene glycol monocaprylate (PGMC) instead of PGML. The results of such evaluation are summarized in Table 7.
上記結果は、PGMCがECD製剤の融合を改善することができ、更なる硬化プロセス無しでの放出制御コーティングとして許容される結果をもたらすということを証明している。 The above results demonstrate that PGMC can improve the fusion of ECD formulations and give acceptable results as a controlled release coating without further curing process.
(実施例9)
PGMLとECD−30の混合物の安定性
アクアコート(登録商標)ECD−30を、8.9%PGML(分散液中のエチルセルロース固体の重量に基づく)と混ぜて、室温条件下(20℃から25℃)及び上昇させた条件下(40℃、75%RH)で3ヶ月間置いておいた。そのような貯蔵の後、TEC及び他の成分を添加し、混合物を15%固体濃度に希釈した。テオフィリンペレットをコーティングして、得られた固体剤形を実施例3に示した手順に従って評価した。このような評価の結果を表8に要約する。
Example 9
Stability of a mixture of PGML and ECD-30 Aquacoat® ECD-30 was mixed with 8.9% PGML (based on the weight of ethylcellulose solids in the dispersion) at room temperature conditions (from 20 ° C. to 25 ° C. ° C) and elevated conditions (40 ° C, 75% RH) for 3 months. After such storage, TEC and other ingredients were added and the mixture was diluted to 15% solids concentration. The theophylline pellets were coated and the resulting solid dosage form was evaluated according to the procedure shown in Example 3. The results of such evaluation are summarized in Table 8.
上記結果は、この発明の水性懸濁液は、高湿度及び上昇させた温度条件下でさえも、長期間にわたって貯蔵安定性であることを示している。 The above results show that the aqueous suspensions of this invention are shelf stable over long periods even under high humidity and elevated temperature conditions.
(付記)
(付記1)
(i)水、(ii)エチルセルロース、(iii)イオン性界面活性剤、及び、(iv)3から8のHLB値を有する有機エステルである融合助剤を含む水性懸濁液を、コーティングを形成するように、活性成分を含む固体コアに適用することを含む、放出制御固体剤形を製造する方法。
(Appendix)
(Appendix 1)
An aqueous suspension comprising (i) water, (ii) ethylcellulose, (iii) an ionic surfactant, and (iv) a fusion aid that is an organic ester having an HLB value of 3 to 8 forms a coating. A process for producing a controlled release solid dosage form comprising applying to a solid core comprising an active ingredient.
(付記2)
前記融合助剤は、3.5から7のHLB値を有する、付記1に記載の方法。
(Appendix 2)
The method of claim 1, wherein the coalescing aid has an HLB value of 3.5 to 7.
(付記3)
前記融合助剤は、4から5のHLB値を有する、付記2に記載の方法。
(Appendix 3)
The method of claim 2, wherein the fusion aid has an HLB value of 4 to 5.
(付記4)
前記融合助剤は、C5−C17飽和又は不飽和脂肪族炭化水素部分を含む、付記1から3のいずれか1つに記載の方法。
(Appendix 4)
The coalescing agent, C 5 -C 17 contains a saturated or unsaturated aliphatic hydrocarbon moiety, A method according to any one of Appendixes 1 3.
(付記5)
前記融合助剤は、ソルビタンエステル及びプロピレングリコールモノエステルからなる群から選択される、付記4に記載の方法。
(Appendix 5)
The method according to appendix 4, wherein the fusion aid is selected from the group consisting of sorbitan ester and propylene glycol monoester.
(付記6)
前記融合助剤は、プロピレングリコールモノラウレート及びソルビタンモノオレエートからなる群から選択される、付記5に記載の方法。
(Appendix 6)
6. The method according to appendix 5, wherein the fusion aid is selected from the group consisting of propylene glycol monolaurate and sorbitan monooleate.
(付記7)
前記融合助剤は、前記エチルセルロースの総重量に基づき、4重量%と30重量%との間の量で存在する、付記1から6のいずれか1つに記載の方法。
(Appendix 7)
The method according to any one of appendices 1 to 6, wherein the coalescing aid is present in an amount between 4 wt% and 30 wt% based on the total weight of the ethylcellulose.
(付記8)
前記界面活性剤は、アニオン性界面活性剤である、付記1から7のいずれか1つに記載の方法。
(Appendix 8)
The method according to any one of appendices 1 to 7, wherein the surfactant is an anionic surfactant.
(付記9)
前記界面活性剤は、アルキルサルフェートである、付記8に記載の方法。
(Appendix 9)
The method according to appendix 8, wherein the surfactant is an alkyl sulfate.
(付記10)
前記界面活性剤は、ラウリル硫酸ナトリウムである、付記9に記載の方法。
(Appendix 10)
The method according to appendix 9, wherein the surfactant is sodium lauryl sulfate.
(付記11)
前記水性懸濁液は、可塑剤を更に含む、付記1から10のいずれか1つに記載の方法。
(Appendix 11)
The method according to any one of appendices 1 to 10, wherein the aqueous suspension further comprises a plasticizer.
(付記12)
前記可塑剤は、ジブチルセバケート、ジエチルフタレート、トリエチルシトレート、トリブチルシトレート、ポリエチレングリコール、プロピレングリコール及びトリアセチンからなる群から選択される、付記11に記載の方法。
(Appendix 12)
The method of claim 11, wherein the plasticizer is selected from the group consisting of dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, polyethylene glycol, propylene glycol, and triacetin.
(付記13)
付記1から12のいずれか1つに記載の方法により製造される、固体剤形。
(Appendix 13)
A solid dosage form produced by the method according to any one of appendices 1 to 12.
(付記14)
a)水、b)エチルセルロース、c)イオン性界面活性剤、及び、d)3から8のHLB値の有機エステルである融合助剤、を含む、放出制御コーティングを製造するのに適した水性懸濁液組成物。
(Appendix 14)
An aqueous suspension suitable for producing a controlled release coating comprising: a) water, b) ethylcellulose, c) an ionic surfactant, and d) a fusion aid that is an organic ester having an HLB value of 3 to 8. A suspension composition.
(付記15)
前記融合助剤は、3.5から7のHLB値を有する、付記14に記載の組成物。
(Appendix 15)
15. The composition of claim 14, wherein the coalescing aid has an HLB value of 3.5 to 7.
(付記16)
前記融合助剤は、4から5のHLB値を有する、付記15に記載の組成物。
(Appendix 16)
The composition of claim 15, wherein the coalescing aid has an HLB value of 4 to 5.
(付記17)
前記融合助剤は、C5−C17飽和又は不飽和脂肪族炭化水素部分を含む、付記14から16のいずれか1つに記載の組成物。
(Appendix 17)
The coalescing agent, C 5 -C 17 saturated or unsaturated containing aliphatic hydrocarbon moiety A composition according to any one of Supplementary Note 14 16.
(付記18)
前記融合助剤は、ソルビタンエステル及びプロピレングリコールモノエステルからなる群から選択される、付記17に記載の組成物。
(Appendix 18)
The composition according to appendix 17, wherein the fusion aid is selected from the group consisting of sorbitan ester and propylene glycol monoester.
(付記19)
前記融合助剤は、プロピレングリコールモノラウレート及びソルビタンモノオレエートからなる群から選択される、付記18に記載の組成物。
(Appendix 19)
Item 19. The composition according to item 18, wherein the fusion aid is selected from the group consisting of propylene glycol monolaurate and sorbitan monooleate.
(付記20)
前記融合助剤は、前記エチルセルロースの総重量に基づき、4重量%と30重量%との間の量で存在する、付記14から19のいずれか1つに記載の組成物。
(Appendix 20)
20. The composition according to any one of appendices 14 to 19, wherein the fusion aid is present in an amount between 4% and 30% by weight based on the total weight of the ethylcellulose.
(付記21)
前記界面活性剤は、アニオン性界面活性剤である、付記14から20のいずれか1つに記載の組成物。
(Appendix 21)
The composition according to any one of appendices 14 to 20, wherein the surfactant is an anionic surfactant.
(付記22)
前記水性懸濁液は、可塑剤を更に含む、付記14から21のいずれか1つに記載の組成物。
(Appendix 22)
The composition according to any one of appendices 14 to 21, wherein the aqueous suspension further comprises a plasticizer.
Claims (21)
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US5273760A (en) | 1991-12-24 | 1993-12-28 | Euroceltigue, S.A. | Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer |
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